Multicomponent NMR Titration for Simultaneous Measurement of Relative pK_as

An NMR titration method has been developed to simultaneously measure the difference in acid dissociation constants (ΔpK_a) of two or more compounds with high precision and accuracy. The ΔpK_a between the conjugate acids of the two stereoisomers of 4-tert-butylcyclohexylamine 1 was determined in a single ¹H NMR titration experiment. A mixture of the two stereoisomers was titrated with DCl in a 3:1 (v/v) mixture of CD₃OD/D₂O. From the variations of the H1 chemical shifts the ratio of the acidity constants was determined. The trans stereoisomer 1_t was found to be the more basic by 0.121 ± 0.002 pK unit. A repeat titration in DMSO-d₆ also found 1_t to be the more basic, by 0.217 ± 0.003 pK unit. The ΔpK_a between the two stereoisomers of 4-tert-butylcyclohexanecarboxylic acid 2 was determined in both of these solvents using ¹H and ¹³C NMR. Thermodynamic parameters ΔΔH° and ΔΔS° were evaluated from the temperature dependence of ΔpK_a. To further demonstrate the utility of this method, the ΔpK_as of the conjugate acids of the four stereoisomers of 2-decalylamine 3 were determined in a single ¹H NMR titration experiment. The cis,cis stereoisomer (3_cc) was found to be the most basic, with the cis,trans (3_ct), trans,cis (3_tc), and trans,trans (3_tt) less basic by 0.012 ± 0.003, 0.037 ± 0.004, and 0.141 ± 0.005 pK unit, respectively. A second four-component titration was also performed with the two 4-tert-butylcyclohexylamines (1) and the two trans-2-decalylamines (3_tc, 3_tt).